Therapeutic agents useful for treating pain

Abstract

A compound of formula: wherein X is S or O and A, R 1 , R 2 , R 3 , R 4 , n, and m are disclosed herein, or a pharmaceutically acceptable salt thereof (a “Pyridazinylpiperazine Compound”), compositions comprising a Pyridazinylpiperazine Compound, and methods for treating or preventing pain, UI, an ulcer, IBD and IBS in an animal comprising administering to an animal in need thereof an effective amount of a Pyridazinylpiperazine Compound are disclosed herein.

1. A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is —NH—, —N(C 1 -C 6 )alkyl-, or —N—(O—C 1 -C 6  alkyl)-; 
 R 1  is -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each R 2  is independently:
 (a) -halo, —OH, or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 R 4  is:
 (a) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (b) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 5  is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
 each R 6  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)OR 7 , or —S(O) 2 R 7 ; 
 each R 7  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each halo is independently —F, —Cl, —Br, or —I; 
 n is an integer ranging from 0 to 2; and 
 m is an integer ranging from 0 to 2. 
 
     
     
       2. The compound of  claim 1 , wherein:
 n is 0; 
 m is 0; and 
 R 4  is phenyl. 
 
     
     
       3. The compound of  claim 2 , wherein the R 4  phenyl is unsubstituted. 
     
     
       4. The compound of  claim 2 , wherein the R 4  phenyl is substituted at the 4-position. 
     
     
       5. The compound of  claim 4 , wherein the R 4  phenyl is substituted with a —CF 3  group, a —OCF 3  group, or a —(C 1 -C 6 ) alkyl group which, optionally, is a tert-butyl group or an iso-propyl group. 
     
     
       6. The compound of  claim 1 , wherein:
 n is 0; 
 m is 1; 
 R 3  is methyl; and 
 R 4  is phenyl. 
 
     
     
       7. The compound of  claim 6 , wherein the R 4  phenyl is unsubstituted. 
     
     
       8. The compound of  claim 6 , wherein the R 4  phenyl is substituted at the 4-position. 
     
     
       9. The compound of  claim 8 , wherein the R 4  phenyl is substituted with a —CF 3  group, a —OCF 3  group, or a —(C 1 -C 6 ) alkyl group which, optionally, is a tert-butyl group or an iso-propyl group. 
     
     
       10. The compound of  claim 1 , wherein A is —NH—. 
     
     
       11. The compound of  claim 1 , wherein A is —N(C 1 -C 6 )alkyl-. 
     
     
       12. The compound of  claim 1 , wherein A is —N—(O—C 1 -C 6  alkyl)-. 
     
     
       13. The compound of  claim 1 , wherein:
 R 4  is:
 (a) —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 1 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (b) -phenyl, -naphthyl, —(C 14 )aryl or —(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups. 
 
 
     
     
       14. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
       15. A method for preparing a composition, comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of  claim 1  and a pharmaceutically acceptable carrier or excipient. 
     
     
       16. A compound of formula (III″): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is —NH— or —N(C 1 -C 6 )alkyl-; 
 R 1  is -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each R 2  is independently:
 (a) -halo, —OH, or —NH 2 , 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 R 4  is -phenyl, which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 5  is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
 each R 6  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
 each R 7  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each halo is independently —F, —Cl, —Br, or —I; 
 n is 0; and 
 m is 1. 
 
     
     
       17. The compound of  claim 16 , wherein A is —NH—. 
     
     
       18. The compound of  claim 16 , wherein A is —N(C 1 -C 6 )alkyl-. 
     
     
       19. The compound of  claim 16 , wherein
 R 3  is methyl. 
 
     
     
       20. The compound of  claim 19 , wherein the R 4  phenyl is unsubstituted. 
     
     
       21. The compound of  claim 19 , wherein the R 4  phenyl is substituted at the 4-position. 
     
     
       22. The compound of  claim 21 , wherein the R 4  phenyl is substituted with a —CF 3  group, a —OCF 3  group, or a —(C 1 -C 6 ) alkyl group which, optionally, is a tert-butyl group or an iso-propyl group. 
     
     
       23. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 16  and a pharmaceutically acceptable carrier or excipient. 
     
     
       24. A method for preparing a composition, comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of  claim 16  and a pharmaceutically acceptable carrier or excipient. 
     
     
       25. A compound of formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is —NH— or —N(C 1 -C 6 )alkyl-; 
 R 1  is -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each R 2  is independently:
 (a) -halo, —OH, or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 R 4  is:
 -phenyl, which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 5  is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
 each R 6  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , —(CH 2 )halo, —OCF 3 , —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
 each R 7  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each halo is independently —F, —Cl, —Br, or —I; 
 n is an integer ranging from 0 to 2; and 
 m is an integer ranging from 0 to 2. 
 
     
     
       26. The compound of  claim 25 , wherein:
 n is 0; and 
 m is 0. 
 
     
     
       27. The compound of  claim 26 , wherein the R 4  phenyl is unsubstituted. 
     
     
       28. The compound of  claim 26 , wherein the R 4  phenyl is substituted at the 4-position. 
     
     
       29. The compound of  claim 28 , wherein the R 4  phenyl is substituted with a —CF 3  group, a —OCF 3  group, or a —(C 1 -C 6 ) alkyl group which, optionally, is a tert-butyl group or an iso-propyl group. 
     
     
       30. The compound of  claim 25 , wherein A is —NH—. 
     
     
       31. The compound of  claim 25 , wherein A is —N(C 1 -C 6 )alkyl-. 
     
     
       32. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 25  and a pharmaceutically acceptable carrier or excipient. 
     
     
       33. A method for preparing a composition, comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of  claim 25  and a pharmaceutically acceptable carrier or excipient. 
     
     
       34. A compound of formula (III′): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A is —NH— or —N(C 1 -C 6 )alkyl-; 
 R 1  is -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each R 2  is independently:
 (a) -halo, —OH, or —NH 2 , 
 (b) -(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 3  is independently:
 (a) -halo, —CN, —OH, —NO 2 , or —NH 2 ; 
 (b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 R 4  is:
 (a) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5  groups; or 
 (b) -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6  groups; 
 
 each R 5  is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
 each R 6  is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ; 
 each R 7  is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); 
 each halo is independently —F, —Cl, —Br, or —I; 
 n is an integer ranging from 0 to 2; and 
 m is an integer ranging from 0 to 2. 
 
     
     
       35. The compound of  claim 34 , wherein:
 n is 0; and 
 m is 0. 
 
     
     
       36. The compound of  claim 34 , wherein:
 n is 0; 
 m is 1; and 
 R 3  is methyl. 
 
     
     
       37. The compound of  claim 34 , wherein A is —NH—. 
     
     
       38. The compound of  claim 34 , wherein A is —N(C 1 -C 6 )alkyl-. 
     
     
       39. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of  claim 34  and a pharmaceutically acceptable carrier or excipient. 
     
     
       40. A method for preparing a composition, comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of  claim 34  and a pharmaceutically acceptable carrier or excipient.